This new proposal entitled Immune enhancement for immunological non-responders to ART details a novel clinical trial of dietary zinc and S-adenosylmethionine (SAMe) supplementation in individuals infected with the human immunodeficiency virus (HIV) who do not respond adequately to anti-retroviral therapy (ART). Specifically, approximately 35% of HIV-infected individuals who are treated with appropriate doses of ART and achieve virological control nevertheless do not recover a healthy immune response and remain at high risk for lung infections and chronic lung diseases, and have worse overall health outcomes. The mechanisms underlying this high failure rate are unknown, but older age and chronic alcohol use are associated with increased risk of immunological non-responsiveness. HIV infection is associated with zinc deficiency and oxidative stress, and we have compelling experimental and clinical evidence that these factors are particularly problematic in the alveolar space where they impair host immune functions in the alveolar macrophage. Specifically, otherwise healthy individuals with HIV infection or chronic alcohol ingestion have evidence of oxidative stress (as reflected by changes in thiol anti-oxidants such as glutathione), zinc deficiency, and impaired alveolar macrophage capacity to ingest and kill bacteria. Provocatively, treating these macrophages with zinc and/or glutathione improves their phagocytic capacity. In experimental models we have determined that dietary supplementation with zinc and/or glutathione precursors such as SAMe restore a healthy redox state and zinc bioavailability within the alveolar space and thereby normalize alveolar macrophage immune function. These studies are supported by other clinical evidence that zinc supplementation appears to decrease the progression of immune failure in HIV-infected individuals, and that SAMe supplementation has salutary effects on HIV-related depression. Taken together, the experimental and clinical evidence strongly argues that a combination of zinc and SAMe will restore redox and immune health in the airways of immunological non-responders, and could have salutary systemic immune effects as well. Using a multidisciplinary team that includes established clinical investigators in HIV clinical trials at Emory University and the University of Washington, translational lung biology scientists, and sophisticated state-of-the-art research platforms in metabolomics, genomics, and redox biochemistry, we will assess both the lung-specific and the systemic responses to this therapy. Our larger goal is to identify novel features and/or mechanisms underlying immunological non-responsiveness and thereby develop and test therapies that can enhance the effects of ART and convert 'non-responders' to 'responders'. We have a uniquely qualified team that is focused on extending and improving the overall health of these individuals using targeted therapeutic approaches that are safe, simple, and feasible for broad delivery both in our society as well as in societies where healthcare resources are much scarcer.